The present invention relates to a liquid formulation of metformin and salts thereof and to the use thereof in treating hyperglycemia and/or diabetes.
Diabetes Mellitus is the most common of the serious metabolic diseases affecting humans. It has been estimated that there are over 200 million people that have diabetes in the world.
Metabolically, diabetes is characterized by an inappropriate elevation of blood glucose levels. In Type I Diabetes Mellitus, this is due to an absence of insulin in the individual. In Type II Diabetes Mellitus, although there is circulating insulin, its signal is not efficiently transduced via the insulin receptor, giving rise to insulin resistance, where the body responds less and less well to a given amount of insulin. Insulin is a peptide hormone which is produced by the Langerhorn islets in the pancreas. Insulin triggers increased glucose utilization, protein synthesis, and the formation and storage of neutral lipids. The present invention focuses on Type II Diabetes Mellitus, or non-insulin-dependent diabetes.
Diabetes Mellitus is also characterized by long term complications involving the eyes, nerves, kidneys and blood vessels. These diabetic complications include premature atherosclerosis, intercapillary glomerulosclerosis, retinopathy and neuropathy. The major cause of morbidity and mortality among diabetics is coronary heart disease.
The primary goal in the treatment of diabetes is to maintain blood glucose levels as close to normal as possible. For Type II diabetics, the first line of therapy for maintaining blood glucose level is modification of diet and lifestyle. The diabetic diet features restrictions on fat content and an increased intake of dietary fiber. Regular exercise is also emphasized to decrease weight and reduce the degree of insulin resistance.
If diet and lifestyle modifications fail to control glucose levels, oral hypoglycemic therapy or insulin therapy is required to control glucose levels and thus minimize complications related to the disease.
One of the compounds used to treat diabetes is metformin or its pharmaceutically acceptable salts. Metformin is a dimethyl biguanide having the formula: 
The pharmaceutically acceptable salts of the formula 
in which A is the anion of the non-toxic salt are the preferred medicaments.
U.S. Pat. No. 3,174,921 to Sterne discloses various pharmaceutically acceptable salts of metformin, for example, phosphate, sulfate, hydrochloride, salicylate, maleate, benzoate, ethanedisulfonate, fumarate and glycolate. U.S. Pat. No. 6,031,004 to Timmins, et al. discloses metformin salts of dibasic acids, such as fumarate and succinate, wherein the molar ratio of metformin:dibasic acid is 2:1.
However, the most preferred metformin product is the hydrochloride salt. In fact, the biguanide anti-hyperglycemic agent, metformin, is currently marketed in the U.S. in the form of its hydrochloride salt. (Glucophage(copyright), Bristol-Myers Squibb Company).
Metformin hydrochloride is a cohesive white powder which is highly soluble in water ( greater than 300 mg/ml at ambient temperature). The market metformin hydrochloride salt has a pronounced saline, bitter taste. Accordingly, it is usually marketed as a coated tablet wherein its coating is masked or is designed to mask any unpleasant taste.
Unfortunately, as sold, the tablet is very large, making it different to swallow. Moreover, due to its size, this drug cannot be used by children or adults who are not able to swallow tablets. However, the present inventors realize that a liquid formulation would be useful for children and adults who cannot swallow large size tablets or orally intake chewable tablets.
To date, no one has heretofore made a liquid formulation of metformin hydrochloride salt which has masked the unpleasant taste thereof. Moreover, to date, no one has made a liquid formulation of metformin or salt thereof.
The preparation of a liquid formulation for masking the bitter taste of metformin or its salts is not straightforward, as one might think. After all, the skilled artisan would expect that the taste could be masked by adding a sugar. However, since the liquid formulation is being used to treat diabetes, sugar cannot be used. Moreover, in addition to being sugar free, the liquid formulation should contain none or a minimal amount of sodium salt since it detrimental to diabetic patients. Moreover, it should contain little or no alcohol (ethanol) since ethanol is detrimental to diabetic patient. Furthermore, metformin and its salts, especially the hydrochloride salts are so bitter, it has heretofore been difficult to completely mask the taste without the use of sugar, alcohol and sodium salts.
The present inventors have also found a means of making the metformin in the liquid formulation palatable to patients.
The present invention is directed to a liquid pharmaceutical composition for oral administration to a subject in need thereof which comprises a therapeutically effective amount of metformin or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable liquid carrier.
In a preferred embodiment, the present invention is directed to a liquid formulation of metformin or its pharmaceutically acceptable salts, wherein the formulation comprises a therapeutically effective amount of metformin in a liquid carrier, containing a sweetener or polyhydroxy alcohol. In one preferred embodiment, the liquid carrier contains at least one of the following components: a polyhydroxy alcohol, a sweetener that does not raise the alcohol sugar level when ingested by a mammal, or an alkyl hydroxyethylcellulose. In a more preferred embodiment, the liquid formulation of the present invention contains at least two of the additional components and most preferably all three additional components. It is most preferred, in this embodiment, that the liquid formulation comprises a therapeutically effective amount of metformin or its pharmaceutically acceptable salts, about 40% to about 80% by weight of a sweetener, about 5% to about 55% by weight polyhydroxy alcohol and about 0.01% to about 5% by weight alkyl hydroxyethylcellulose.
In another embodiment, the liquid formulation comprises a therapeutically effective amount of metformin or its pharmaceutically acceptable salt, a sweetener or mixture of sweeteners that do not raise the alcohol sugar level when ingested by a mammal, and a mineral acid and bicarbonate salt, such that the pH of the formulation ranges from about 4 to about 9. In this formulation, the acid and bicarbonate salt are present in an amount sufficient to maintain the formulation in a pH ranging from about 4.0 to about 9.0. In this embodiment, it is preferred that the sweetener is a mixture of a sugar alcohol and non-nutritive sugar.
The present invention is also directed to a method of treating hyperglycemia which comprises administering to a patient in need of treatment an antihyperglycemic effective amount of said liquid formulation. In another embodiment, the present invention is directed to a method for treating Type II diabetes in a patent which comprises administering to a patent in need of treatment an anti-diabetic effective amount of said liquid formulation.
As used herein, the term xe2x80x9cpatientxe2x80x9d refers to an animal who is suffering from hyperglycemia or diabetes. The preferred animal is a mammal, such as dogs, cats, horses, cows and humans. It is preferred that the patient is a human.
As described hereinabove, an aspect of the present invention is directed to a liquid formulation comprising a therapeutically effective amount of metformin or its pharmaceutically acceptable salts in association with a liquid carrier.
Metformin and various pharmaceutically acceptable salts are described in U.S. Pat. Nos. 3,174,901 and 6,031,004, the contents of which are incorporated by reference. Examples include mono and dibasic acid salts of metformin, including the hydrochloride salt, the phosphate salts, sulfate salts, hydrobromide salts, salicylate salts, maleate salt, benzoate salt, succinate salt, ethane disulfonate salt, fumarate salt, glycolate salt and the like. The pharmaceutical composition of the present invention contains a therapeutically effective amount of metformin or its pharmaceutically acceptable salts thereof. By xe2x80x9ctherapeutically effective amountxe2x80x9d of metformin is meant that amount of metformin or its pharmaceutically acceptable salt which either maintains or reduces the concentration of sugar in the blood of the patient, depending upon the severity of the disease. The therapeutically effective amount is determined by an ordinarily skilled artisan, taking into account various considerations, such as the age of the subject, the weight of the subject, the condition of the patient, the type of patient (i.e., the type of animal), the regimen, the desired result and the like. The amount prescribed is determined by physicians, who may adjust the dosage regime received by the patients. For example, several divided dosages may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. For example, in a preferred embodiment, the metformin or its pharmaceutically acceptable salts are administered to the patient in amounts as described for the hydrochloride, as set forth in the Physician""s Desk Reference. Preferably, a therapeutic effective amount of metformin or salt thereof ranges from about 10 mg/kg/day to about 40 mg/kg/day and more preferably from about 14 mg/kg/day to about 38 mg/kg/day. The liquid formulation of the present invention contains a therapeutically effective amount of metformin or its pharmaceutically acceptable salts. Preferably, the liquid formulation contains metformin or its pharmaceutically acceptable salts in an amount ranging from about 20 mg/ml to about 400 mg/ml and more preferably from about 40 mg/ml to about 200 mg/ml and, most preferably, from about 50 mg/ml to about 100 mg/ml.
The metformin, or its pharmaceutically acceptable salts are in association with a liquid carrier. The liquid form, as contemplated by the present invention, include solutions, suspensions, syrups and emulsions and only suspension (e.g., mix formulation in oily liquid vehicle). Inasmuch as the pharmaceutical composition is for oral administration, the liquid carrier is one that is normally utilized as a liquid carrier in pharmaceutical formulations and preparations, except that the liquid carrier should not contain excessive alcohol (ethanol). The ethanol, if present, is present in minimal amounts, e.g., no more than about 1% (v/v) or more preferably no more than about 0.5% (v/v). The liquid carrier may be an aqueous liquid, such as water, a non-aqueous liquid, such as glycols, e.g., propylene glycol or polyethylene glycol, vegetable oil, an oil-in-water emulsion or a water-in-oil liquid emulsion, or an aqueous dispersion, such as in glycol, liquid polyethylene glycol, vegetable oil and mixture thereof. The preferred liquid carrier is water.
It is preferred that the liquid formulation of the present invention is syrupy. It is even more preferred that the viscosity of the liquid formulation is near or greater than 1. Inasmuch as the liquid formulation flows, the upper limit is the maximum viscosity that a flowing liquid can have. It is preferred that the viscosity of the liquid formulation of the present invention ranges from about 5 to about 50 cps, and more preferably, from about 10 to about 40 cps, and more preferably, from about 15 to about 35 cps and most preferably about 25 cps. Moreover, it is preferred that the density of the liquid formulation of the present invention is one g/mL or greater, with the maximum value being that value a flowing liquid can have. It is preferred that the density of the liquid at 25xc2x0 C. is between 1 g/mL and 2 g/mL and more preferably between 1.05 g/mL and 1.5 g/mL and more preferably between 1.1 g/mL and 1.3 g/mL.
In a first embodiment, the present liquid formulation comprises the metformin or its pharmaceutically acceptable salts thereof, the liquid carrier and at least one or two of the following: a sweetener, a polyhydric alcohol, an alkyl hydroxy ethyl cellulose, or combination thereof. It is most preferred that it contains all three components.
As indicated herein above, in this embodiment, the liquid formulation a preferably contains polyhydric alcohols. The term polyhydric alcohol means any organic polyalcohol containing more than one hydroxy group thereon. It includes propylene glycol, dipropylene glycol, polyethylene glycol, glycerin, butylene glycol, hexylene glycol, polyoxyethylene, polypropylene glycol, sorbitol or other sugar alcohol, ethylene glycol and the like. When the polyhydric alcohol is a polymer, such as polyethylene glycol, it is preferred that the number of hydroxy groups thereon is about the same as the number of carbon atoms present. If not a polymer, it is preferred that the alkyl moiety contains 2 to 6 carbons and 2 to 6 hydroxy groups. Such polyhydric alcohols include glycols, triols and polyols having 2, 3, 4, 5 to 6 alcoholic hydroxy groups per molecule or per repeating unit of the polymer. Typical of said glycols are glycols containing 2 to 10 carbon atoms, e.g., ethylene glycol, propylene glycol, butylene glycol and polyethylene glycol (average molecular weight ranging from about 200 to about 8000 daltons and more preferably from about 200 to about 6000 daltons), and most preferably from about 200 to about 2000 daltons, and the like. Examples of said triols include glycerin, trimethylol propane, and the like. Other examples of polyols include sorbitol, polyvinyl pyrrolidone, and the like. In this embodiment, however, it is preferred that the polyol is not a sugar (carbohydrate) or sugar alcohol; it is preferred that the polyhydroxy alcohols are glycols, triols, or polymers and the like, e.g., alkanes or polymers comprised of repeating alkylene units, wherein the alkanes or repeating alkylene units in the polymers are substituted by at least 3 to 6 hydroxy groups. These polyhydric alcohols may be used either singly or in combination. If used in combination, it is preferred that two or three different polyhydric alcohols are used. The most preferred polyhydric alcohol is polyethylene glycol, preferably having a molecular weight ranging from about 200 daltons to about 2000 daltons and more preferably from about 400 daltons to about 1600 daltons. A polyethylene glycol having a molecular weight greater than 1000 daltons provides the syrupy texture that is preferably desired in the formulation of the present invention and is effective in masking the bitter taste of metformin and its salts. However, as the molecular weight of the polyethylene glycols increases, it becomes more and more viscous and the liquid containing same becomes thicker and more difficult with which to work. At the higher molecular weights, the polyethylene glycol begins to adopt more solid-like properties. Furthermore, the greater the molecular weight the less of the polyethylene glycol used in the formulation. Thus, it is preferred that the polyethylene glycol when present is a mixture of polyethylene glycol of 1000 daltons or less and a polyethylene glycol greater than 1000 daltons. It is within the skill of one ordinary skill in the art to mix the various types of polyethylene glycols to obtain a liquid formulation of desired viscosity, especially having a viscosity within the ranges and preferred ranges indicated herein above.
The polyhydric alcohols are present in amounts in the liquid formulation ranging from about 5 to about 55% by weight and, more preferably, from about 15 to about 40% by weight and most preferably from about 20% to about 30% by weight. If polyethylene glycol is the polyhydric alcohol, it is preferred that it is a mixture of polyethylene glycol having a molecular weight greater than 1000 daltons and 1000 daltons or less. Moreover it is preferred that the weight ratio of polyethylene glycol of 1000 daltons or less to the polyethylene glycol of greater than 1000 daltons ranges from about 1:1 to about 6:1 and more preferably from about 5:1 to about 4:1 and most preferably from about 1:2:1 to about 3:1. It is preferred that the weight ratio of polyhydric alcohol to sweetener, if present, ranges from about 1:1 to about 6:1 and, more preferably, from about 1.5:1 to about 4:1 and, most preferably, from about 2:1 to about 3:1.
In addition, the weight ratio of polyhydric alcohol to alkyl hydroxyethyl-cellulose, if present, ranges from about 50:1 to about 400:1 and more preferably from about 100:1 to about 400:1, and most preferably, from about 200:1 to about 300:1.
The weight ratio of metformin or its pharmaceutically acceptable salt to polyhydric alcohol preferably ranges from about 1:2 to about 4:1, and more preferably from about 1:1 to about 3:1, and most preferably from about 1.5:1 to about 2:1.
In this first embodiment, the liquid formulation preferably contains a sweetener (i.e., a compound that imparts a sweet taste but does not increase the blood glucose levels of the patient). Examples include a sugar alcohol and non-nutritive sugars.
As used herein, the term sugar alcohol refers to reduced sugars. The preferred sugar alcohol are mono-saccharide alcohols and disaccharide alcohols. The monosaccharide alcohols have the formula HOxe2x80x94CH2(CHOH)nxe2x80x94CH2OH, wherein n is 2-5. They also include tetritols, pentitols, hexitols and heptitols. Examples of sugar alcohols include erythritol, theritol, ribitol, arabinitol, xylitol, allitol, dulcitol, glucitol, sorbitol, mannitol, altritol, iditol, maltitol, lactitol, isomalt, hydrogenated starch hydrolysate and the like. The sugar alcohols, especially the monosaccharide alcohols, may be utilized as a racemic mixture or in the D or L form.
The non nutritive sweeteners are patentably sweet but are non-caloric. Examples include L-sugars, aspartame, alitame, acesulfame-K, cyclamate, stevioside, glycyrrhizin, sucralose, neohesperidin, dihydrochalcone, thaumatin saccharin and its pharmaceutically acceptable salts (e.g., calcium), and the like.
In this embodiment of the present formulation, it is preferred that the sweetener be present in the liquid formulation in amounts ranging from about 40% to about 80% by weight and more preferably from about 50% to about 70% and most preferably from about 55% to about 65%. In addition, it is preferred that the weight ratio of sweetener to alkyl hydroxyethyl cellulose, when present, ranges from about 400 to about 800, and, most preferably, from about 500 to about 600.
In this embodiment, the ratio of sweetener to metformin or its pharmaceutically acceptable salt ranges from about 8:1 to about 1:1, and, more preferably, from about 6:1 to about 2:1 and, most preferably, from about 5:1 to about 3:1.
Another component that is preferably present in the first embodiment of the liquid formulation of the present invention is an alkyl hydroxyethyl-cellulose. This is produced stepwise or by simultaneous reaction of ethylene oxide and a hydrophobic alkylating reagent known in the art. As used herein, with respect to this term, the alkyl group contains preferably from 1 to 24 carbon atoms and more preferably from 2 to 15 carbon atoms, and most preferably, from 2 to 10 carbon atoms. Examples include ethylhydroxy ethyl cellulose (EHEC) manufactured by Berol Kemi AB under the Bermocoll trade name and hydroxy ethyl cellulose (HEC), modified with a long chain alkyl group, generally termed HMHEC (HM=Hydrophobically Modified) manufactured by Aqualon Cot sold under the trade name Natrosol Plus, and the like.
The alkyl hydroxyethylcellulose, when present in this embodiment, is present in the liquid formulation in an amount ranging from about 0.01 to about 5% by weight, and more preferably from about 0.05 to about 1% by weight and most preferably from about 0.08 to about 0.2% by weight. The weight ratio of alkyl hydroxyethylcellulose, when present, to metformin or its pharmaceutically acceptable salt ranges from about 1:300 to about 1:50 and more preferably, from about 1:200 to about 1:100.
In this first embodiment, it is preferred that the liquid formulation of the present invention contains metformin or its pharmaceutically acceptable salts, the sweetener, the alkyl hydroxyethylcellulose and the polyhydroxy alcohol in association with the liquid carrier, in the amounts described herein.
In a second embodiment, the pharmaceutical liquid formulation of the present invention contains the metformin in pharmaceutically effective amounts as described hereinabove and the liquid carrier, as defined hereinabove. In addition, the pharmaceutical liquid formulation also contains a sweetener, as defined hereinabove. The sweetener is present in an amount ranging from about 10% to about 70% of the liquid formulation and more preferably is present in an amount ranging from about 20% to about 60% and most preferably from about 30% to about 50% (w/w). It is most preferred that the sweetener in this embodiment is a mixture of two sweeteners, a sugar alcohol, as defined hereinabove and a non-nutritive sweetener, as defined hereinabove. It is preferred that the sugar alcohol is present in amounts greater than the non-nutritive sweetener. More preferably, the weight ratio of the sugar alcohol to non-nutritive sweetener preferably ranges from about 700:1 to about 85:1 and more preferably ranges from about 300:1 to about 100:1 and more preferably from about 200:1 to about 110:1.
In addition, it is preferred in this embodiment that the weight ratio of metformin to sweetener ranges from about 1:35 to about 1:1 and more preferably from about 1:20 to about 1:10 and most preferably from about 1:15 to about 1:5.
Besides the sweetener, and the metformin and the liquid carrier, it is preferred that the pH of the formulation is about 4.0 or greater. The present inventors have found that when the pH is greater than about 4.0, the bitter taste of the metformin is greatly reduced. However, the formulation cannot be too basic for at high pH""s, it may be harmful to the animal or mammal. It is preferred that the pH ranges from about 4.0 to about 9.0 and more preferably from about 4.2 to about 7.0 and most preferably ranging from about 4.3 to about 5.1.
Base and/or acid may be added to the formulation to control the pH.
However, it is most preferred that the acid is a mineral acid, that is, it completely dissociates when placed in water at 25xc2x0 C. Examples include e.g., hydrochloric acid, sulfuric acid, nitric acid and the like. Hydrochloric acid is the most preferred. Although HCl(g) may be dissolved in the liquid formulation, it is preferred that hydrochloric acid be utilized.
The base that is utilized is a bicarbonate salt. Any bicarbonate salt which is not toxic or harmful especially to diabetics can be used. The preferred salts are potassium salts.
Without wishing to be bound, it is believed that the mineral acid and bicarbonate salts present with the metformin, causes in-situ formation and release of effervescent gas (carbon dioxide, which carbonation helps in the taste masking of metformin liquid in pH range of about 4.0 to about 9.0 and more preferably in the desired pH ranges indicated hereinabove, along with the sugar alcohol and non-nutritive sweetener.
The pharmaceutical liquid formulation of the present invention may, in addition contain optional ingredients. For example, the liquid formulation comprising metformin or its pharmaceutically acceptable may include another antihyperglycemic agent.
The metformin or salt thereof may be in combination with one or more antihyperglycemic agents. Moreover, the metformin alone or in combination with one or more antihyperglycemic agents may also be employed in combination with amylin.
The antihyperglycemic agent may be an oral antihyperglycemic agent, e.g., a sulfonyl urea, such as glyburide (also known as glibenclamide), glimepride (disclosed in U.S. Pat. No. 4,379,785, the contents of which are incorporated by reference), glipizide, gluclazide, or chloropropamide or other known sulfonyl ureas or other antihyperglycemic agents which act on the ATP-dependent channel of the B cells. The preferred sulfonylurea are glyburide and glipizide.
Where present, the sulfonyl ureas, such as glyburide, glimepiride, glipyride, glipizide, chlorpropamide and gliclazide and the glucosidase inhibitors acarbose or miglitol may be employed in formulation amounts and dosing as indicated in the Physician""s Desk Reference.
The metformin or salt thereof is preferably employed in a weight ratio to the sulfonylurea in the range from about 50:1 to about 300:1, and more preferably, from about 75:1 to about 250:1.
The antihyperglycemic agent may also be a glucosidase inhibitor, such as acarbose (disclosed in U.S. Pat. No. 4,904,769, the contents of which are incorporated by reference) or miglitol (disclosed in U.S. Pat. No. 4,639,436, the contents of which are incorporated by reference).
The metformin or salt thereof is preferably employed in a weight ratio to the glucosidase inhibitor within the range from about 2:1 to about 300:1 and more preferably from about 25:1 to about 200:1.
The antihyperglycemic agent may be a thiazolinedione oral anti-diabetic agent (which has an insulin sensitivity effect in Patents with Type II diabetes) such as trogliltazone (Warner Lambert""s Rezuline(copyright), disclosed in U.S. Pat. No. 4,572,912, the contents of which are incorporated by reference), zorglitazone (Smith-Kline Beecham), pioglitazone (Takeda) Mitsubishi""s MCC-555 (disclosed in U.S. Pat. No. 5,594,016, the contents of which are incorporated by reference), Glaxo-Welcome""s GL-262570, englitazone (CP-68722 Pfizer) or darglitazone (CP-86325, Pfizer).
The metformin or salt thereof is preferably employed in a weight ratio to the thiazolidinedione in an amount within the range from about 0.1:1 to about 75:1 and more preferably from about 0.5:1 to about 5:1.
Where present, the thiazolidinedione anti-diabetic agent may be employed in amounts within the range from about 0.01 to about 2000 mg/day which may be administered in single or divided doses one to four times per day.
The metformin or salt thereof may also be employed in combination with a non-oral antihyperglycemic agents such as insulin or with glucagon-like peptide-1 (GLP-1) such as GLP-1(1-36) amide, GLP-1(7-36) amide, GLP-1(7-37) (as disclosed in U.S. Pat. No. 5,614,492 to Habener, the disclosure of which is incorporated herein by reference).
Where present insulin may be employed in formulations, in the amounts and dosing as indicated by the Physician""s Desk Reference.
Where present GLP-1 peptides are administered in the liquid oral formulation of the present invention.
Other optional ingredients which may be present in the liquid formulations of the present invention include buffers, such as citric acid or its corresponding salts or acetic acids and its salts; flavoring agents, such as peppermint, oil of wintergreen, orange, or cherry flavoring, and the like, surfactants, thickeners, preservatives, such as methyl and propyl parabens, and the like; anti-oxidants, such as benzoate salts, and the like; chelating agents, such as EDTA and its salts and the like.
It is preferred that the liquid formulation is buffered having a pH ranging from about 4.0 to about 9.0 and more preferably from about 4.2 to about 7.0 and, most preferably from about 4.3 to about 5.1. These pH ranges may be effetted by one of ordinary skill in the art using conventional buffer systems, such as critic acid and citrate, and the like.
In addition, in accordance with the present invention, a method is provided for treating hyperglycemia including Type II diabetes (NIDDM) comprising administering to a patient in need thereof a liquid pharmaceutical composition comprising metformin or its pharmaceutically acceptable salts, in accordance with the present invention.
The liquid fotmulation of the present invention may be prepared by any of the known methods of pharmacy, but all methods include the step of bringing into association the metformin or the salt thereof, and optionally, the sweetener or mixture of sweeteners, if present, the alkyl hydroxyethylcellulose and the polyhydroxy alcohol or acid and base and the optional ingredients, with the liquid carrier. In general, the pharmaceutical compositions are prepared by uniformly and intimately mixing these various components with the liquid carrier. For example, aqueous solutions suitable for oral use can be prepared by dissolving the aforementioned and desired components in water and adding, if desired, additional optional ingredients such as suitable colorants, flavors, stabilizing and thickening agents, and the like, as desired. Aqueous suspensions suitable for oral use can be made by dispersing the, finely divided metformin or its pharmaceutically acceptable salt and the desired components, e.g., the sweetener or mixture of sweetening, if present the acid and or base, if present, the polyhydroxy alcohol, if present, the alky hydroxy ethyl cellulose, if present, and the other optional ingredients in water with viscous material normally used in the pharmaceutical arts to make dispersions, such as natural or synthetic gums, resins, methylcellulose, sodium carboxyethylcellulose and other well-known suspending agents.
It is to be understood that the ingredients used in the present formulation are non-toxic.
Unless indicated to the contrary, it is to be understood that the percentages are by weight. Moreover, it is to be understood that the percentages are of the dry weight of the formulation, excluding the weight of the liquid carrier. For example, if the carrier is water, it represents the dry weight of the formulation.
However, inasmuch as these formulations are to be administered to diabetics, the formulation does not contain sugars such as glucose, sucrose, and the like, which would increase the blood glucose levels of the patients. Moreover, in a preferred embodiment, the formulation of the present invention does not contain sodium salts. Furthermore, the liquid pharmaceutical composition of the present invention contains at most, minimal alcohol that is about 1% (v/v) or less and more preferably 0.5% (v/v) or less.
In addition, the singular denotes the plural and vice versa.
Furthermore, the terms polyhydroxy alcohol and polyhydric alcohol, as used herein, are synonymous, and are used interchangeably without changing the meaning.
Moreover, unless indicated to the contrary, the liquid carrier is relatively purified. For example, if water is the carrier, it is purified (distilled water) or deionized water.